Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023
Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study.
Клиническое исследование I фазыСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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de Braud Filippo, Dooms Christophe, Heist Rebecca S, Lebbe Celeste, Wermke Martin, Gazzah Anas, Schadendorf Dirk, Rutkowski Piotr, Wolf Jürgen, Ascierto Paolo A, Gil-Bazo Ignacio, Kato Shumei, Wolodarski Maria, McKean Meredith, Muñoz Couselo Eva, Sebastian Martin, Santoro Armando, Cooke Vesselina, Manganelli Luca, Wan Kitty, Gaur Anil, Kim Jaeyeon, Caponigro Giordano, Couillebault Xuân-Mai, Evans Helen, Campbell Catarina D, Basu Sumit, Moschetta Michele, Daud Adil
Аннотация
PURPOSE: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.
PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).
RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.
CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.
PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).
RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.
CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.